Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets

Bioorg Med Chem Lett. 2008 Feb 1;18(3):1063-6. doi: 10.1016/j.bmcl.2007.12.010. Epub 2007 Dec 10.


Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism*
  • Combinatorial Chemistry Techniques*
  • Crystallography, X-Ray
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry
  • Guanidines / pharmacology*
  • Molecular Conformation
  • Molecular Structure
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Guanidines
  • N-(2-(2,5-diphenyl-pyrrol-1-yl)-acetyl)guanidine
  • Pyrroles
  • Amyloid Precursor Protein Secretases